African trypanosomiasis or the “sleeping sickness” is a parasitic disease caused by various species of the protozoa Trypanosoma brucei that is transmitted by the Tsetse fly[1]. T. brucei is transmitted through the bite and saliva of the Tsetse fly of the genus Glossina that is found solely in Africa along the equator [2]. The particular subspecies of T. brucei that this particular write up will be focused on is the T. b. gambiense which causes a chronic from of the disease. A person infected with this form of the disease could potentially live months or even years without any major symptoms and yet 95% of reported cases of the sleeping sickness are this kind [1]. Chronic African trypanosomiasis (caused by T. b. gambiense) uses humans as a reservoir and is common in central and western Africa.
FIGURE 1: Map of the distribution of African trypanosomiasis cases on the continent of Africa [1]. African trypanosomiasis can also be transmitted from mother-to-child as the protozoa (T. b. gambiense) are capable of crossing the placenta [1]. The disease is classified as either stage 1 or stage two “depending on whether parasites have become manifest in the cerebrospinal fluid” and the treatments vary slightly at each stage [2]. Stage 1 is noted by inflammation at the site of infection and tends to be accompanied by lymphadenopathy “frequently in the posterior triangle of the neck” [2]. In stage two, parasites invade the internal organs and can occur in the span of a few weeks or in the case of T. b. gambiense, several months.
Full-size image (140 K)
FIGURE 2: Life cycle of T. cruzei and T. brucei, both of which cause a form of the African sleeping sickness [1].
Symptoms include, but are not limited to: anxiety, insomnia, mood changes, swelling lymph nodes, sweating, headaches, fevers, and weakness [1]. This disease is of particular importance in third world countries where their lack of both preventative measures and resources for treatment make them more susceptible. African trypanosomiasis affects approximately half a million people and causes approximately 50,000 deaths per year [2]. A related disease to the “sleeping sickness” is Chagas disease which is caused by the T. cruzi parasite. Africa has experienced several sleeping sickness epidemics in the past century and while the number of reported infections has decreased, the WHO estimated about 50 – 70,000 new cases in 2004 [3].
Drug Information
Melarsoprol is an arsenic-based drug used in the treatment of the second stage of African trypanosomiasis for over 50 years and must be administered intravenously [3]. Due to it being arsenic-based, there can be adverse side effects to melarsoprol treatment including: skin reactions, fever, pain in the chest, and motor and sensitivity polyneuropathies [4]. One of the more adverse reactions is reactive encephalopathy which has a fatality of 3 -10% [1]. Reactive encephalopathy is a condition of the brain and in this case can include: headache, tremors, slurred speech, and even coma. There is a suggested treatment schedule of ten consecutive daily doses of 2.16 mg/kg that was created from a trial involving monkeys [4]. There is also a high rate of relapse after melarsoprol treatment indicative of growing drug resistance by T. b. gambiense. Another drug is available under the name eflornithine that has been more effective with less adverse side effects [3]. Unfortunately, due to its’ high cost of synthesis and lack of resources in the affected areas (mainly poverty stricken Africa), eflornithine is only used in specific situations [4]. Melarsoprol itself is not used for any other application than the treatment of trypanosomiasis and is sometimes known under the name Mel B. Melarsoprol is not solely patented, but it is included in a patent for a method of treating leukemia by using a dosage of melarsoprol. According to clinicaltrials.gov which is a database for national trials, there was a study done in conjunction Uganda in 2006 involving late-stage gambiense trypanosomiasis and melarsoprol as a treatment.
FIGURE 3: Molecular structure of Melarsoprol
Target Information
Melarsoprol is a melaminophenyl arsenical used as an antritrypanosomiasis reagent. Although it has been in use for many years, there is still little known about how it exactly operates on a molecular level. It is known that Mel B “inhibits glycolytic enzymes, phosphogluconate dehydrogenase and trypanothione reductase” [5]. Glycolytic enzymes are involved in the process of glycolysis which is essential in the synthesis of ATP. Phosphogluconate dehydrogenase is an enzyme that is also needed for ATP synthesis by helping in the pentose phosphate pathway. In a study done involving yeast (Schizosaccharomyces pombe) it was shown to interfere with thiamine metabolism. This study was important because yeast is usually used in labs as a simple model of a eukaryotic system and T. b. gambiense has a fairly standard eukaryotic cell structure (other than its’ variable surface glycoprotein coat that allows it to avoid the hosts immune system). Thiamine is essential in cells and a deficiency of it can lead to cell death since it acts as a cofactor of other enzymes [5]. Melarsoprol is also thought to work in the treatment of African trypanosomiasis by disrupting the active sites of many enzymes used by T. b. gambiense due to their formation by sulfhydryl groups. The drug ends up inactivating pyruvate kinase (which can be found in the cell cytoplasm) which then inhibits the production of ATP and leads to cell death.
References
[1] Trypanosomiasis, Human African (sleeping sickness). http://www.who.int/mediacentre/factsheets/fs259/en/. (accessed February 3rd, 2013).
[2] Barrett, M. P.; Burchmore, R. J.; Stich, A.; Lazzari, J. O.; Frasch, A. C.; Cazzulo, J. J.; Krishna, S., The trypanosomiases. The Lancet2003,362 (9394), 1469-1480.
[3] Malvy, D.; Chappuis, F., Sleeping sickness. Clinical Microbiology and Infection2011,17 (7), 986-995.
[4] Blum, J.; Burri, C., Treatment of late stage sleeping sickness caused by T. b. gambiense: a new approach to the use of an old drug. Swiss Medical Weekly 2002,132, 51-56.
[5] Schweingruber, M. E., The Melaminophenyl Arsenicals Melarsoprol and Melarsen Oxide Interfere with Thiamine Metabolism in the Fission Yeast Schizosaccharomyces pombe. Antimicrobial Agents and Chemotherapy2004,48 (9), 3268-3271.
Disease/Drug of Interest
African trypanosomiasis/MelarsoprolMotivation and Background
African trypanosomiasis or the “sleeping sickness” is a parasitic disease caused by various species of the protozoa Trypanosoma brucei that is transmitted by the Tsetse fly[1]. T. brucei is transmitted through the bite and saliva of the Tsetse fly of the genus Glossina that is found solely in Africa along the equator [2]. The particular subspecies of T. brucei that this particular write up will be focused on is the T. b. gambiense which causes a chronic from of the disease. A person infected with this form of the disease could potentially live months or even years without any major symptoms and yet 95% of reported cases of the sleeping sickness are this kind [1]. Chronic African trypanosomiasis (caused by T. b. gambiense) uses humans as a reservoir and is common in central and western Africa.FIGURE 1: Map of the distribution of African trypanosomiasis cases on the continent of Africa [1].
African trypanosomiasis can also be transmitted from mother-to-child as the protozoa (T. b. gambiense) are capable of crossing the placenta [1]. The disease is classified as either stage 1 or stage two “depending on whether parasites have become manifest in the cerebrospinal fluid” and the treatments vary slightly at each stage [2]. Stage 1 is noted by inflammation at the site of infection and tends to be accompanied by lymphadenopathy “frequently in the posterior triangle of the neck” [2]. In stage two, parasites invade the internal organs and can occur in the span of a few weeks or in the case of T. b. gambiense, several months.
FIGURE 2: Life cycle of T. cruzei and T. brucei, both of which cause a form of the African sleeping sickness [1].
Symptoms include, but are not limited to: anxiety, insomnia, mood changes, swelling lymph nodes, sweating, headaches, fevers, and weakness [1]. This disease is of particular importance in third world countries where their lack of both preventative measures and resources for treatment make them more susceptible. African trypanosomiasis affects approximately half a million people and causes approximately 50,000 deaths per year [2]. A related disease to the “sleeping sickness” is Chagas disease which is caused by the T. cruzi parasite. Africa has experienced several sleeping sickness epidemics in the past century and while the number of reported infections has decreased, the WHO estimated about 50 – 70,000 new cases in 2004 [3].
Drug Information
Melarsoprol is an arsenic-based drug used in the treatment of the second stage of African trypanosomiasis for over 50 years and must be administered intravenously [3]. Due to it being arsenic-based, there can be adverse side effects to melarsoprol treatment including: skin reactions, fever, pain in the chest, and motor and sensitivity polyneuropathies [4]. One of the more adverse reactions is reactive encephalopathy which has a fatality of 3 -10% [1]. Reactive encephalopathy is a condition of the brain and in this case can include: headache, tremors, slurred speech, and even coma. There is a suggested treatment schedule of ten consecutive daily doses of 2.16 mg/kg that was created from a trial involving monkeys [4]. There is also a high rate of relapse after melarsoprol treatment indicative of growing drug resistance by T. b. gambiense. Another drug is available under the name eflornithine that has been more effective with less adverse side effects [3]. Unfortunately, due to its’ high cost of synthesis and lack of resources in the affected areas (mainly poverty stricken Africa), eflornithine is only used in specific situations [4]. Melarsoprol itself is not used for any other application than the treatment of trypanosomiasis and is sometimes known under the name Mel B. Melarsoprol is not solely patented, but it is included in a patent for a method of treating leukemia by using a dosage of melarsoprol. According to clinicaltrials.gov which is a database for national trials, there was a study done in conjunction Uganda in 2006 involving late-stage gambiense trypanosomiasis and melarsoprol as a treatment.FIGURE 3: Molecular structure of Melarsoprol
Target Information
Melarsoprol is a melaminophenyl arsenical used as an antritrypanosomiasis reagent. Although it has been in use for many years, there is still little known about how it exactly operates on a molecular level. It is known that Mel B “inhibits glycolytic enzymes, phosphogluconate dehydrogenase and trypanothione reductase” [5]. Glycolytic enzymes are involved in the process of glycolysis which is essential in the synthesis of ATP. Phosphogluconate dehydrogenase is an enzyme that is also needed for ATP synthesis by helping in the pentose phosphate pathway. In a study done involving yeast (Schizosaccharomyces pombe) it was shown to interfere with thiamine metabolism. This study was important because yeast is usually used in labs as a simple model of a eukaryotic system and T. b. gambiense has a fairly standard eukaryotic cell structure (other than its’ variable surface glycoprotein coat that allows it to avoid the hosts immune system). Thiamine is essential in cells and a deficiency of it can lead to cell death since it acts as a cofactor of other enzymes [5]. Melarsoprol is also thought to work in the treatment of African trypanosomiasis by disrupting the active sites of many enzymes used by T. b. gambiense due to their formation by sulfhydryl groups. The drug ends up inactivating pyruvate kinase (which can be found in the cell cytoplasm) which then inhibits the production of ATP and leads to cell death.References
[1] Trypanosomiasis, Human African (sleeping sickness). http://www.who.int/mediacentre/factsheets/fs259/en/. (accessed February 3rd, 2013).[2] Barrett, M. P.; Burchmore, R. J.; Stich, A.; Lazzari, J. O.; Frasch, A. C.; Cazzulo, J. J.; Krishna, S., The trypanosomiases. The Lancet 2003, 362 (9394), 1469-1480.
[3] Malvy, D.; Chappuis, F., Sleeping sickness. Clinical Microbiology and Infection 2011, 17 (7), 986-995.
[4] Blum, J.; Burri, C., Treatment of late stage sleeping sickness caused by T. b. gambiense: a new approach to the use of an old drug. Swiss Medical Weekly 2002, 132, 51-56.
[5] Schweingruber, M. E., The Melaminophenyl Arsenicals Melarsoprol and Melarsen Oxide Interfere with Thiamine Metabolism in the Fission Yeast Schizosaccharomyces pombe. Antimicrobial Agents and Chemotherapy 2004, 48 (9), 3268-3271.
External Links
http://www.infectionlandscapes.org/2011/04/trypanosomiasis-part-1-sleeping.html